Preliminary findings in our laboratory indicate that intercalating agents, and also polylysine, stimulate epsilon N-methylation of certain internal histone lysine residues in rat-liver nuclei incubated in the presence of S-adenosyl-methionine. The same agents had no effect or inhibited the activity of the isolated nuclear lysine N-methyltransferase. This pronounced effect by a relatively small change in DNA structure suggests that the polar, methylatable part of arginine-rich histone molecules, DNA and methyltransferase are situated in close proximity in the chromatin complex. Intercalating agents can therefore be used to probe chromatin structure by this approach. In addition, polysine was also found to stimulate this process under the same conditions, with a maximum appearing at lysine/phosphate ration: 0.5. We propose to extend these studies as follows: 1. A study on the effect of pH and ionic strength and phase of the cell cycle on intercalation and stimulation of histone N-methylation by intercalating agents in isolated nuclei and chromatin. (Activity, histone fractions involved, moiety of me-lysine). 2. Compare the effect of intercalating agents on histone methylation in condensed and diffuse chromatin, and in isolated 115 chromatin particles. 3. A study on the effect of the composition of chromatin on stimulation by removing certain histone fractions or non-histone proteins from chromatin. 4. Effect on reconstituted DNA/histone/enzyme complexes in which the histone content is varied. 5. The effect of intercalation on the other histone modifications: Acetylation and phosphorylation.